Oligomer diversity during the aggregation of the repeat-region of tau

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Oligomer diversity during the aggregation of the repeat-region of tau. / Kjaergaard, Magnus; Dear, Alexander J.; Kundel, Franziska; Qamar, Seema; Meisl, Georg; Knowles, Tuomas P.J.; Klenerman, David.

In: ACS Chemical Neuroscience, Vol. 9, No. 12, 2018, p. 3060-3071.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Kjaergaard, M, Dear, AJ, Kundel, F, Qamar, S, Meisl, G, Knowles, TPJ & Klenerman, D 2018, 'Oligomer diversity during the aggregation of the repeat-region of tau', ACS Chemical Neuroscience, vol. 9, no. 12, pp. 3060-3071. https://doi.org/10.1021/acschemneuro.8b00250

APA

Kjaergaard, M., Dear, A. J., Kundel, F., Qamar, S., Meisl, G., Knowles, T. P. J., & Klenerman, D. (2018). Oligomer diversity during the aggregation of the repeat-region of tau. ACS Chemical Neuroscience, 9(12), 3060-3071. https://doi.org/10.1021/acschemneuro.8b00250

CBE

Kjaergaard M, Dear AJ, Kundel F, Qamar S, Meisl G, Knowles TPJ, Klenerman D. 2018. Oligomer diversity during the aggregation of the repeat-region of tau. ACS Chemical Neuroscience. 9(12):3060-3071. https://doi.org/10.1021/acschemneuro.8b00250

MLA

Vancouver

Kjaergaard M, Dear AJ, Kundel F, Qamar S, Meisl G, Knowles TPJ et al. Oligomer diversity during the aggregation of the repeat-region of tau. ACS Chemical Neuroscience. 2018;9(12):3060-3071. https://doi.org/10.1021/acschemneuro.8b00250

Author

Kjaergaard, Magnus ; Dear, Alexander J. ; Kundel, Franziska ; Qamar, Seema ; Meisl, Georg ; Knowles, Tuomas P.J. ; Klenerman, David. / Oligomer diversity during the aggregation of the repeat-region of tau. In: ACS Chemical Neuroscience. 2018 ; Vol. 9, No. 12. pp. 3060-3071.

Bibtex

@article{54b431480d454a4d8c076f6c7e3e37f8,
title = "Oligomer diversity during the aggregation of the repeat-region of tau",
abstract = "The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here we have used single molecule fluorescence techniques combined with mechanistic modelling to study the heparin-induced aggregation of the repeat region of tau, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguish several sub-populations of oligomers with different stability and follow their evolution during aggregation reactions as a function of temperature and concentration. Employment of techniques from chemical kinetics reveals that the two largest populations structurally distinct from fibrils; and are both kinetically and thermodynamically unstable. The first population is in rapid exchange with monomers and held together by electrostatic interactions; the second is kinetically more stable, dominates at later times and is probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer induced effects in the cellular environment, for example by overloading protein quality control systems. We also show that the shortest growing filaments remain suspended in aqueous buffer and thus comprise a third, smaller population of transient oligomers with cross-i¢ structure. Overall our data show that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.",
keywords = "aggregation mechanism, amyloid oligomers, kinetic modeling, single-molecule FRET, tau",
author = "Magnus Kjaergaard and Dear, {Alexander J.} and Franziska Kundel and Seema Qamar and Georg Meisl and Knowles, {Tuomas P.J.} and David Klenerman",
year = "2018",
doi = "10.1021/acschemneuro.8b00250",
language = "English",
volume = "9",
pages = "3060--3071",
journal = "A C S Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "12",

}

RIS

TY - JOUR

T1 - Oligomer diversity during the aggregation of the repeat-region of tau

AU - Kjaergaard, Magnus

AU - Dear, Alexander J.

AU - Kundel, Franziska

AU - Qamar, Seema

AU - Meisl, Georg

AU - Knowles, Tuomas P.J.

AU - Klenerman, David

PY - 2018

Y1 - 2018

N2 - The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here we have used single molecule fluorescence techniques combined with mechanistic modelling to study the heparin-induced aggregation of the repeat region of tau, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguish several sub-populations of oligomers with different stability and follow their evolution during aggregation reactions as a function of temperature and concentration. Employment of techniques from chemical kinetics reveals that the two largest populations structurally distinct from fibrils; and are both kinetically and thermodynamically unstable. The first population is in rapid exchange with monomers and held together by electrostatic interactions; the second is kinetically more stable, dominates at later times and is probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer induced effects in the cellular environment, for example by overloading protein quality control systems. We also show that the shortest growing filaments remain suspended in aqueous buffer and thus comprise a third, smaller population of transient oligomers with cross-i¢ structure. Overall our data show that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.

AB - The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here we have used single molecule fluorescence techniques combined with mechanistic modelling to study the heparin-induced aggregation of the repeat region of tau, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguish several sub-populations of oligomers with different stability and follow their evolution during aggregation reactions as a function of temperature and concentration. Employment of techniques from chemical kinetics reveals that the two largest populations structurally distinct from fibrils; and are both kinetically and thermodynamically unstable. The first population is in rapid exchange with monomers and held together by electrostatic interactions; the second is kinetically more stable, dominates at later times and is probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer induced effects in the cellular environment, for example by overloading protein quality control systems. We also show that the shortest growing filaments remain suspended in aqueous buffer and thus comprise a third, smaller population of transient oligomers with cross-i¢ structure. Overall our data show that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.

KW - aggregation mechanism

KW - amyloid oligomers

KW - kinetic modeling

KW - single-molecule FRET

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=85049355385&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.8b00250

DO - 10.1021/acschemneuro.8b00250

M3 - Journal article

C2 - 29953200

AN - SCOPUS:85049355385

VL - 9

SP - 3060

EP - 3071

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

SN - 1948-7193

IS - 12

ER -